Various roles of interferons and their receptors in Coxsackievirus B3 pathogenesis during oral infection in mice 4234

Description The leading cause of viral myocarditis, Coxsackievirus B3 (CVB3), is an enterovirus that racks up millions of infections annually and can also cause meningitis and HFMD. While mouse studies with intraperitoneal infections have shown the need for type I interferons (IFN-I) in controlling CVB3 replication, the protection mechanism and how individual IFN subtypes shape pathogenesis during a natural infection remains understudied. Here, we orally infected wild type C57Bl/6 (B6), Ifnar1=/=, several IFN-I KOs, and IFN-III receptor-deficient (Ifnlr1-/-) mice with the CVB3-N63Y, a mouse-adapted variant of the CVB3 Nancy strain. Only the Ifnar1-/- males showed weight loss and succumbed to infection, while the females, B6 and all IFN-I knockout strains survived. The detection of virus already in the spleen, heart, liver, and the pancreas, but not in the mesenteric lymph node of the Ifnar1-/- mice at 1 day post infection, suggested that systemic viral spread does not require replication in the gut. In agreement, the Ifnlr1-/- mice were resistant to infection. B6 mice controlled early viral spread in the secondary lymphoid organs and the heart but not in the liver (males) and pancreas (both sexes). The resistance of Ifnar1Vav-Cre mice suggests that IFNAR is required in non-hematopoietic cells for protection. Our data shows that CVB3 becomes rapidly systemic via the oral route, independent of sex and genotype, and protection in males requires IFNAR in non-hematopoietic cells. Funding Sources 5R01AI169460 Topic Categories Viral Immunology (VIR)